2-(3-carboxyl and 3-carbamyl-pyridinium) succinic acid betaines and a method for their preparation



United States Patent Ofiice 3,3l2,7l2 Patented Apr. 4, 1967 Thisinvention is concerned with certain novel substituted pyridinederivatives and with a processfor their preparation.

The new compounds of this invention are betaines of the formula:

fe on--ooo CHz-COOH where R is a carboxyl group or a carbonamide group,the nitrogen atom of which may, if desired, be substi tuted with one ormore lower alkyl groups.

These new betaines may be prepared by taking advantage of the specialproperty of some pyridine tertiary amines to add themselves to thedouble bond of unsaturated organic acids according to the followingreaction diagram:

(l) Formation of the pyridine maleate ion (I) (2) Betainification, bytransfer of the hydrogen atom of ion (I) to the beta-carbon atom of theethylenic bond:

In carrying out the reaction, the maleic acid is generated in situ fromD-l-bromosuccinic acid.

I The following examples are given by way of illustration only:

EXAMPLE 1 2-(3-carbamyl-pyridinium) succinic acid betaine CONHz err-cCHr-COOH 24.4 g. (0.2 ml.) of nicotinic amide was dissolved in 200 ml.of ethanol at C. To this solution was added 39.4 g. (0.2 ml.) ofD-l-bromosuccinic acid dissolved in 200 ml. of ethanol at 95 C. Thissolution is kept at 50 C. for 3 hours. The solution was thenconcentrated to a volume of ml. and an excess of silver hydroxide insuspension in water, i.e., 0.3 ml. in 100 ml. of water, was added. Themixture was brought to a temperature of 90 C., it Was agitated for 5minutes and then the silver salts were eliminated by filtration.

The crude product was recrystallized from boiling Water.2-(3-carbamyl-pyridinium) succinic acid betaine was obtained in a yieldof 50% as a pure product with the following characteristics.

Crystalline form: white prismatic rods.

Instantaneous melting temperature on block: +245 C.

Analysis (C H O N Calculated: C=50.4l%, H=4.23%, N=1l.76%. Found:C=50.5%, H=4.l9%, N=11.7l%.

In an alternative method of preparation, the silver hydroxide isreplaced by an ion-exchange resin for example, Amberlite resin,

EXAMPLE 2 2-(3-diethylcarbamyl pyridinillm) succinic acid betainemonohydrate 9 CH-C o 0 ,1120

CHr-COOH The process was carried out as in Example 1 except that thenicotinamide was replaced by N,N-diethylnicotinamide. The resultsobtained were comparable with those obtained in Example 1.

2-(3-diethylcarbamyl-pyridinium) succinic acid betaine was obtained inthe monohydrated form in a yield of 40%, as a product with the followingcharacteristics.

Crystalline form: white rods.

Instantaneous melting point on block=l53 C.

Analysis (C H O N H O): Calculated: C=53.5%, H=6.35%, N=7.8%. Found:C=53.4%, H=6.2%, N=7.8%.

The new betaines have valuable lipotropic properties and are suitablefor human administration as lipotropic agents. The invention accordinglyincludes pharmaceutical preparations containing the new betaines.

In human medicine, these betaines exhibit lipotropic properties at thehepatic cell and vascular endothelium level, making them suitable astherapeutic agents particularly for the treatment of hepatic disordersand disorders of the vascular wall, atheromatosis and atherosclerosis.

These properties can be demonstrated pharmacologically on animals inwhich a metabolic disorder has been induced either by prolonged fast orby lipidic overload, and in such cases the compounds have the effect ofreducing the percentage of total hepatic fatty acids or increasing thepercentage of lipotropic acidity determinable by Draegstedts formula, orthe effect of providing protection against chloroform poisoning.

3 4 Test 1.-Co1np=arison of the biological results obtained chloroformsolution (5% in groundnut oil) in accordance with rabbits which hadreceived a lipidic overload in acwith G. E. Pagets technique Toxi andApplied Pharm,

cordance with the technique described in detail in Agresso- 1961, 3,595-605, in: logic, 1963, IV, 45-51, in animals which during the sixdays following the cessation of the overloading had 135- Animals treatedwith 2-(3-carb amyl-pyridinium) succinic ceived 200 mg./kg. of2-(3-carbamylpyridinium) succinic 5 acid betaine in a dose of 400*mg./kg. orally during acid betaine orally in suspension containing gumarabic, the 2 days preceding and just before the chloroform and incontrols which had received only the lipidic overinjection, and then 3and 6 hours afterwards; load, showed that: Untreated animals receivingthe same injection;

(i) The above-mentioned betaine reduces the percent- 10 Controls,

ages of hepatic fatty acids.

(ii) The percentage of lipotropic activity of this bet i showed thatthis betaine effectively protects the mouse is very high and greaterthan that of choline. from chloroform poisoning, the percentage of thereduc- The results obtained a tabulat d b l tion of total hepaticlipides being 58.3% as against 38.1%

Controls Controls which did not Betaine Choline receive overload Totalhepatic fatty acids, g./100 gv of dry liver 12.14 18. 43 10.87 10. OS:lz2. 37 i1. 90 :lzl. 22 :l:0. 52 Colde tr cted he at'cl' ides, .100 .of(1r 1iver 1.21 2.98 3.26 1.96 X a p 1 1p g g y i0. 049 :|:0. 67 :|:0. 78:!:0. 34

Percentage of lipotropic activity 93.3 v 92.7

The Perfentage of hpotroplc actlvlty 1S Obtamed by in the case ofcholine under the same experimental condi- Draegstedt s formula: tionsThe results obtained are tabulated below:

Controls Percent Controls plus Betaine decrease chloroform Coldextracted hepatic lipides, g. per 100 g. of dry liver 5: 3: 5g, 3

For human administration, the new betaines are conveniently administeredorally in the form of hard gelatin L g giz x fig hpldes m per 100 ofhver of capsules containing 500 mg. of the active compound. For S is thenumber dbtained under the same conditions for the treatment of 'hfapatlcdlsorders sultable dosage is 2 to 6 g. of the actlve compound daily andfor the treat- ".Jmreated slck i i h f ment of degenerativecardio-vascular diseases, a suitable C is the number obtained on er t esame con them or dosage is 4 to 8 g of the active compound daily for 15where ammals on a normal dlet' days each month for 3 successive months.

Test 2.--Comparison of the biological results obtained We laim; withrabbits in which a metabolic disturbance of endogen' 1. A process forthe preparation of a 2-(3-substitutedous origin produced by a fast of 6days (Arnmerman, C. B.; pyridinium) succinic acid betaine, the pyridinering of & A- 1961, causes an increase in which is substituted in the3-position by a group selected hepatic biosynthesis of cholesterol inthe animals which from the group consisting of carboxyl, carbonamide, N-during the last three days of the test had received 200 (loweralkyl)-c-arbonarnide and N,N-di(lower alkyl)- rn-g./-kg. orally of2-(3-carblamyl-pyridinium) succinic acid carbonamide, which comprisesthe step of reacting a pyrbetaine, and in controls which had onlyundergone the fast, idine derivative selected from the group alkyl)substituted showed that: nicotinic acid, nicotinamide, N-(loweralkyl)-substituted This betaine gave a marked reduction of thepropornicotinarnides and N,N-di(lower alkyl)-substituted nicotion ofhepatic fatty acids. Its percentage of lipotropic tinamides, withD-l-bromosuccinic acid in the presence of activity is very significant.silver hydroxide under conditions whereby said bromos-uc- The resultsobtained are tabulated below: cinic acid is converted to maleic acid insitu.

2. A process for the preparation of a 2-(3-substituted- Controlspyridinium) succinic acid betaine, the pyridine ring of Controlssubjected Bewine which is substituted 1n the 3-pos1ton by a groupselected o fasting from the group consisting of carboxyl,carbonamide,-N-

' (lower alkyl)-carbona-mide and N,N-di(lower alkyl)-cara ahatht e.a2:;;;;;;;;;; the at: t e; g h h whhhh hhhhhhhh hh Shh hh h h h hhPercentage ompotmpic activity 56.1 erivatlve selected from the groupconsistlng of n1cot1n1c acid, nicotinamide, N-(lower alkyl)-substitutednicotinamides and N,N-di(1ower alkyD-substituted nicotinamides,

Test 3.Comparison of the biological results obtained withD-l-lbromosuccinic acid in the presence of an ion-exwith mice in Which afatty degeneration of the liver was prochange resin under conditionswhereby said bromosuccinic duced by subcutaneous injection of 1.25 ml./kg. of an oily acid is converted to maleic acid in situ.

3,312,712 5 6 3. Betaines of the formula: carbomamide, N-(loweraIkyD-caIbOnamid'e and N,N-di- (lower a1kyl)-carbonamide.

4. 2-(3-carboxyl-pyridiniu-m) succinic acid betaine.

R 5. 2-(3-carbamyl-pylidinium) succinic acid betaine.

6. 2- (3 diethylcarbamyl pyridinium) succinic acid \N betaine.

I 69 9 References Cited by the Examiner FFCOO Lutz: Berichte Jahrg: 431910 pages 2636-40. CH2-C 0 OH 10 WALTER A. MODANCE, Primal Examiner.

where R is elected from the group consisting of carboxyl, ALAN ROTMAN,Assistant Examiner-

1. A PROCESS FOR THE PREPARATIONS OF A 2-(3-SUBSTITUTEDPYRIDINIUM)SUCCINIC ACID BETAINE, THE PYRIDINE RING OF WHICH IS SUBSTITUTED IN THE3-POSITION BY A GROUP SELECTED FROM THE GROUP CONSISTING OF CARBOXY,CARBONAMIDE, N(LOWER ALKYL)-CARBONAMIDE AND N,N-DI(LOWERALKYL)CARBONAMIDE, WHICH COMPRISES THE STEP OF REACTING A PYRIDINEDERIVATIVE SELECTED FROM THE GROUP ALKYL)-SUBSTITUTED NICOTINIC ACID,NICOTINAMIDE, N-(LOWER ALKYL)-SUBSTITUTED NICOTINAMIDES AND N,N-DI(LOWERALKYL)-SUBSTUTED NICOTINAMIDES, WITH D-1-BROMOSUCCINIC ACID IN THEPRESENCE OF SILVER HYDROXUDE UNDER CONDITIONS WHEREBY SAID BROMOSUCCINICACID IS CONVERTED TO MALEIC ACID IN SITU.